scholarly journals Differential effect of cis-platinum (cis-diamminedichloroplatinum) on regulation of liver and kidney haem and haemoprotein metabolism. Possible involvement of γ-glutamyl-cycle enzymes

1986 ◽  
Vol 237 (3) ◽  
pp. 713-721 ◽  
Author(s):  
M D Maines
Keyword(s):  
Enzyme Activities ◽  
Time Course ◽  
Parent Compound ◽  
Synthetase Activity ◽  
Gamma Glutamyl Transpeptidase ◽  
Gamma Glutamyl ◽  
Differential Effectiveness ◽  
Glutamylcysteine Synthetase ◽  
Ala Synthetase ◽  
Cytochrome P 450

The treatment of rats with cis-platinum (cis-diamminedichloroplatinum) for 1, 3 or 7 days elicited vastly different responses in the liver and the kidney in activities of enzymes of haem-metabolism pathway and gamma-glutamyl-cycle enzymes. The differences resided in the magnitude, direction and the time course of responses. In general, the liver was by far less severely affected, and when a response was elicited, it displayed an earlier onset (1-3 days), with a return to normal at 7 days. In the kidney, however, the effects were notable after 3 days of treatment, and became more pronounced at 7 days. Specifically, the activity of 5-aminolaevulinic acid (ALA) synthetase and contents of cytochrome P-450 and the microsomal haem were decreased in the liver. In contrast, in the kidney, cytochrome P-450 and haem concentrations were significantly increased, with no change in ALA synthetase activity. The increase in the kidney haem content appeared to reflect an increased formation of haem, as suggested by the elevated activity of ferrochelatase and the concomitant decrease in tissue porphyrin levels. In the kidney, a time-dependent and pronounced inhibition of activities of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione production, and gamma-glutamyl transpeptidase, the first enzyme in glutathione breakdown, were observed. The enzyme activities, 7 days after treatment, were only 40 and 60% of the control values respectively. In contrast, these enzyme activities were not affected in the liver. Complexing cis-platinum with cysteine considerably intensified the entire spectrum of effects of cis-platinum in the kidney. Notably, cytochrome P-450 concentration and haem oxygenase activity were increased to about 3.5 and 6 times the control values, respectively. gamma-Glutamylcysteine synthetase activity was decreased to less than 20% of the control. It is suggested that the differential effectiveness of cis-platinum in the liver and the kidney in alternating haem metabolism is related to the vast differences which exist between these organs in the activities of gamma-glutamyl-cycle enzymes. It is further suggested that this may promote the formation in the kidney, but not in the liver, of a cis-platinum-cysteine complex that is more stable, and thus biologically more effective, than the parent compound.

scholarly journals Glutathione replenishment capacity is lower in isolated perivenous than in periportal hepatocytes

1988 ◽  
Vol 254 (2) ◽  
pp. 411-417 ◽  
Author(s):  
Y Kera ◽  
K E Penttilä ◽  
K O Lindros
Keyword(s):  
Glutathione Synthetase ◽  
Synthetase Activity ◽  
Gamma Glutamyl Transpeptidase ◽  
Zonal Distribution ◽  
Significant Difference ◽  
Glutamylcysteine Synthetase ◽  
Gsh Metabolism ◽  
Collagenase Perfusion ◽  
Sulphur Amino Acids ◽  
Glutamyl Transpeptidase

The zonal distribution of GSH metabolism was investigated by comparing hepatocytes obtained from the periportal (zone 1) or perivenous (zone 3) region by digitonin/collagenase perfusion. Freshly isolated periportal and perivenous cells had similar viability (dye exclusion, lactate dehydrogenase leakage and ATP content) and GSH content (2.4 and 2.7 mumol/g respectively). During incubation, periportal cells slowly accumulated GSH (0.35 mumol/h per g), whereas in perivenous cells a decrease occurred (-0.14 mumol/h per g). Also, in the presence of either L-methionine or L-cysteine (0.5 mM) periportal hepatocytes accumulated GSH much faster (3.5 mumol/h per g) than did perivenous cells (1.9 mumol/h per g). These periportal-perivenous differences were also found in cells from fasted rats. Efflux of GSH was faster from perivenous cells than from periportal cells, but this difference only explained 10-20% of the periportal-perivenous difference in accumulation. Furthermore, periportal cells accumulated GSH to a plateau 26-40% higher than in perivenous cells. There was no significant difference in gamma-glutamylcysteine synthetase or glutathione synthetase activity between the periportal and perivenous cell preparations. The periportal-perivenous difference in GSH accumulation was unaffected by inhibition of gamma-glutamyl transpeptidase or by 5 mM-glutamate or -glutamine, but was slightly diminished by 2 mM-L-methionine. This suggests differences between periportal and perivenous cells in their metabolism and/or transport of (sulphur) amino acids. Our results suggest that a lower GSH replenishment capacity of the hepatocytes from the perivenous region may contribute to the greater vulnerability of this region to xenobiotic damage.

Induction of intracellular glutathione in alveolar type II pneumocytes following BCNU exposure

1994 ◽  
Vol 266 (2) ◽  
pp. L125-L130 ◽  
Author(s):  
S. G. Jenkinson ◽  
R. A. Lawrence ◽  
C. A. Zamora ◽  
S. M. Deneke
Keyword(s):  
Intracellular Transport ◽  
Oxidant Stress ◽  
Alveolar Type ◽  
Synthetase Activity ◽  
Type Ii ◽  
Gamma Glutamyl Transpeptidase ◽  
Type Ii Pneumocytes ◽  
Oxidant Damage ◽  
Glutamylcysteine Synthetase ◽  
Glutamyl Transpeptidase

N,N'-bis(2-chloroethyl)-N-nitro-sourea (BCNU) is a potent inhibitor of glutathione reductase (GSSG-Red) activity in both tissues and cells. We examined the effects of treating alveolar type II cells with BCNU and found that a marked decrease in cellular GSSG-Red activity occurred in these cells associated with a time-dependent increase in cellular glutathione (GSH) concentrations. The increase in GSH was not found to be related to changes in cellular gamma-glutamyl transpeptidase activity, gamma-glutamylcysteine synthetase activity, nor increased intracellular transport of cystine. When the BCNU-exposed cells were incubated with hydrogen peroxide to produce oxidant stress, the cells exhibited increased susceptibility to oxidant damage when compared with controls, despite the fact that cellular concentrations of GSH were markedly elevated.

Regulation of cellular glutathione

1989 ◽  
Vol 257 (4) ◽  
pp. L163-L173 ◽  
Author(s):  
S. M. Deneke ◽  
B. L. Fanburg
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cultured Cells ◽  
Feedback Inhibition ◽  
Reductase Activity ◽  
Transport Systems ◽  
Synthetase Activity ◽  
Gamma Glutamyl Transpeptidase ◽  
Gamma Glutamyl ◽  
Glutamyl Transpeptidase

In addition to its participation in a variety of other biochemical reactions, glutathione (GSH) is a major antioxidant. It is regularly generated intracellularly from its oxidized form by glutathione reductase activity that is coupled with a series of interrelated reactions. Synthesis of GSH also takes place intracellularly by a two-step reaction, the first of which is catalyzed by rate-limiting gamma-glutamylcysteine synthetase activity. Intracellular substrates for GSH are provided both by direct amino acid transport and by a gamma-glutamyl transpeptidase reaction that salvages circulating GSH by coupling the gamma-glutamyl moiety to a suitable amino acid acceptor for transport into the cell. Although the liver is a net synthesizer of circulating GSH, organs such as the kidney salvage GSH through the gamma-glutamyl transpeptidase reaction. Intracellular GSH may be consumed by GSH transferase reactions that conjugate GSH with certain xenobiotics. Elevation of cellular GSH levels in cultured cells in response to hyperoxia or electrophilic agents such as diethylmaleate is coupled with an increase in activity of the Xc- transport system for the amino acids cystine and glutamate. Strategies may be developed for protection against oxidant injury by enhancement of transport systems for precursor amino acids of GSH or by providing substrate that circumvents feedback inhibition of GSH synthesis.

scholarly journals Metabolic control mechanisms in mammalian systems. Involvement of adenosine 3′:5′-cyclic monophosphate in androgen action

1971 ◽  
Vol 125 (1) ◽  
pp. 329-342 ◽  
Author(s):  
Radhey L. Singhal ◽  
M. R. Parulekar ◽  
R. Vijayvargiya ◽  
G. Alan Robison
Keyword(s):  
Cyclic Amp ◽  
Enzyme Activities ◽  
Time Course ◽  
Prostate Gland ◽  
Parent Compound ◽  
Seminal Vesicles ◽  
Hepatic Tissue ◽  
Metabolizing Enzymes ◽  
Stimulation Of ◽  
Secondary Sexual

1. The ability of exogenously administered cyclic AMP (adenosine 3′:5′-monophosphate) to exert andromimetic action on certain carbohydrate-metabolizing enzymes was investigated in the rat prostate gland and seminal vesicles. 2. Cyclic AMP, when injected concurrently with theophylline, produced marked increases in hexokinase, phosphofructokinase, glyceraldehyde phosphate dehydrogenase, pyruvate kinase, and two hexose monophosphate-shunt enzymes, as well as α-glycerophosphate dehydrogenase activity in accessory sexual tissues of castrated rats. The 6-N,2′-O-dibutyryl analogue of cyclic AMP caused increases of enzyme activity that were greater than those induced by the parent compound. 3. Time-course studies demonstrated that, whereas significant increases in the activities of most enzymes occurred within 4h after the injection of cyclic AMP, maximal increases were attained at 16–24h. 4. Increase in the activity of the various prostatic and vesicular enzymes was dependent on the dose of cyclic AMP; in most instances, 2.5mg of the cyclic nucleotide/rat was sufficient to elicit a statistically significant response. 5. Administration of cyclic AMP and theophylline also produced stimulation of enzyme activities in secondary sexual tissues of immature rats. 6. Cyclic AMP and theophylline did not affect significantly any of the enzymes studied in hepatic tissue. 7. Stimulation of various carbohydrate-metabolizing enzymes in the prostate gland and seminal vesicles by cyclic AMP was independent of adrenal function. 8. Concurrent treatment with actinomycin or cycloheximide prevented the cyclic AMP- and theophylline-induced increases in enzyme activities in both castrated and adrenalectomized–castrated animals. 9. Administration of a single dose of testosterone propionate (5.0mg/100g) to castrated rats caused a significant increase in cyclic AMP concentration in both accessory sexual tissues. 10. In addition, treatment with theophylline potentiated the effects of a submaximal dose of testosterone (1.0mg/100g) on all those prostatic and seminal-vesicular enzymes that are increased by exogenous cyclic AMP. 11. The evidence indicates that cyclic AMP may be involved in triggering the known metabolic actions of androgens on secondary sexual tissues of the rat.

Drug-Induced Porphyrin Biosynthesis—XII. Levels of Cytochrome P-450 in Chick Embryo Liver following Administration of Allylisopropylacetamide and Propylisopropylacetamide

1974 ◽  
Vol 52 (4) ◽  
pp. 891-895 ◽  
Author(s):  
V. Krupa ◽  
J. C. Creighton ◽  
M. Freeman ◽  
G. S. Marks
Keyword(s):  
Chick Embryo ◽  
Aminolevulinic Acid ◽  
The Other ◽  
Synthetase Activity ◽  
Drug Induced ◽  
Liver Cytochrome ◽  
Time Period ◽  
Embryo Liver ◽  
Ala Synthetase ◽  
Cytochrome P 450

Allylisopropylacetamide caused a decrease in the level of chick embryo liver cytochrome P-450 1 h after administration, followed by an elevation above control levels at a later time period. Propylisopropylacetamide on the other hand did not produce an early decrease in cytochrome P-450 but produced an elevation of cytochrome P-450 at a later time period. Since propylisopropylacetamide is an inducer of δ-aminolevulinic acid synthetase activity and porphyrin accumulation in chick embryo liver, it was concluded that a loss of cytochrome P-450 is not a prerequisite for ALA-synthetase induction as is thought to be the case in rats.

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